• long QT syndrome;
  • electrophysiology;
  • pharmacology;
  • torsades de pointes;
  • M cell;
  • ventricular wall

Combined Congenital and Acquired LQTS. Introduction: A growing number of cardiomyopathies have been shown to result in a reduction in both IKr and IKs, yet little is known about the electrophysiologic and ECG characteristics of combined IKr and IKs block.

Methods and Results: To address this gap in our knowledge, transmembrane action potentials (APs) from epicardial, M, and endocardial cells were recorded simultaneously, together with a transmural ECG from arterially perfused canine left ventricular wedge preparations exposed to combined IKr (d-sotalol; 100 μmol/L) and IKs (chromanol 293B; 30 to 60 μmol/L) block. Under baseline conditions, the T wave was typically upright; epicardium repolarized first, coinciding with the peak of the T wave, and the M cells repolarized last, coinciding with the end of the T wave (Tend). Complex (inverted, biphasic, and triphasic) T waves developed following combined IKr and IKs block. M and epicardial APs prolonged dramatically, so that the endocardial AP was now the earliest to repolarize, coinciding with the first nadir of the complex T wave. In the case of biphasic/triphasic or inverted T waves, Tend coincided with repolarization of either M or epicardial cells, whichever was the last to repolarize. QT intervals prolonged from 286 ± 13 msec up to 744 ± 148 msec and transmural dispersion of repolarization (TDR) increased from 33 ± 10 msec up to 244 ± 71 msec. Early afterdepolarizations (EADs) developed in M and epicardial cells, evoking extrasystoles that precipitated polymorphic ventricular tachycardia. Acceleration-induced EADs and T wave alternans also were observed.

Conclusion: Combined IKr and IKs block gives rise to inverted, biphasic, and triphasic T wave morphologies, a dramatic increase in TDR, and a high incidence of EADs. The diversity of T wave morphologies derives from a preferential AP prolongation of different transmural layers leading to variation in the predominance of voltage gradients on either side of the M cell region. Our study provides direct evidence linking EADs that arise in ventricular epicardial and M cells to the triggered beats that precipitate polymorphic ventricular tachycardia. Our results also suggest possible guidelines for the estimation of TDR from complex T waves appearing in the precordial leads of the surface ECG.